3.2 Prognostic factors of clinical and brain MR imaging characteristics
Tables 2 and 3 show the results of univariate and multivariate analyses of the clinical and brain MR imaging prognosticators of the PFS and OS. The erlotinib group had the best PFS (median PFS 13 months, 95% CI: 11.9–14.1; P = .04). The OS revealed no significant difference among three EGFR-TKI groups. (Fig. 3A and B)
The univariate analysis for prognosticators in PFS revealed that performance status (ECOG 1 vs 0, HR: 1.67, 95% CI: 1.12–2.50; P = .013), tumor characteristics as necrosis (HR: 1.57, 95% CI: 1.06–2.33; P = .026) or rim enhancement (HR: 1.52, 95% CI: 1.04–2.23; P = .031), tumor location at frontal lobe (HR: 1.84, 95% CI: 1.18–2.89; P = .008) or putamen (HR: 1.91, 95% CI: 1.12–3.27; P = .018). The multivariate analysis revealed that the performance status (ECOG 1 vs 0, HR: 1.52, 95%CI: 1.00–2.32; P = .049) and metastasis at frontal lobe (HR: 1.72, 95%CI: 1.08–2.75; P = .023) were associated with PFS.
The univariate analysis for OS revealed that performance status (HR: 1.92, 95%CI: 1.24–2.99; P = .004), tumor characteristics as necrosis (HR: 2.25, 95% CI: 1.46–3.47; P < .001) or rim enhancement (FR: 1.58, 95% CI: 1.03–2.42; P = .035), BM at cerebellum (HR: 1.61 95% CI: 1.06–2.46; P = .026) or putamen (HR: 2.89, 95% CI: 1.67–5.02; P < .001), and second line osimertinib administration (HR: 0.30, 95% CI: 0.17–0.55; P < .001) were associated OS. The multivariate analysis revealed that tumor characteristics as necrosis (HR: 2.84, 95%CI: 1.49–5.40; P = .001), BM at cerebellum (HR: 2.53 95% CI: 1.55–4.14; P < .001) or putamen (HR: 2.62, 95% CI: 1.39–4.91; P = .003), and second line osimertinib administration (HR: 0.26, 95% CI: 0.14–0.50; P < .001) were associated OS. The erlotinib group had marginally superior OS to the gefitinib group (HR 0.57, 95% CI: 0.32–1.00, P = .051).
3.3 PFS and OS of high-risk group patients
The patients with poor prognostic MR imaging features, including tumor necrosis, rim enhancement, and specific tumor locations (frontal lobe, putamen, and cerebellum), were defined as high risk group. Accordingly, we compared the treatment response of three different EGFR-TKIs (erlotinib, afatinib, and gefitinib).
In high risk group, patients treated with erlotinib had a better PFS than gefitinib or afatinib (median PFS 12 versus 6 or 9 months, P < .001) but similar OS (median survival: erlotinib, gefitinib versus afatinib = 20.7, 13.9 vs 16.4 months, P = .137), whereas low risk group patients had similar PFS (median survival: erlotinib, gefitinib versus afatinib = 14, 9, 16 months, P = .517) and OS (median survival: erlotinib, gefitinib vs afatinib = 22.4, 23.5 vs 25.0, P = .865) (Fig. 3C–F).
To the best of our knowledge, this is the first study utilizing brain MRI characteristics as a prognostic factor and response predictor in patents with EGFR-mutated NSCLC treated with different EGFR-TKIs as the first line therapy. Our study results indicated that in patients with NSCLC of EGFR-sensitizing mutation with de novo BM, erlotinib provided better PFS than afatinib or gefitinib but comparable OS as afatinib or gefitinib if the patients had poor prognostic MR characteristics of BM, including tumor necrosis, rim enhancement and specific tumor locations (frontal lobe, putamen and cerebellum). After first line EGFR-TKI failure, the OS was longer in patients with T790M-mutant NSCLC who underwent subsequent osimertinib administration. Therefore, in NSCLC patients with initial BM, subsequent treatment directed by driver gene mutation after first line EGFR-TKI failure might provide more therapeutic effect and survival benefit than conventional chemotherapy.
The previous studies have shown certain MR imaging characteristics were associated with gene mutation status of the primary tumor and were predictor for OS. However, these studies did not further focus on the association between brain MRI characteristics and prognosis, and had minimal impact on the treatment decision. There have been a few publications focusing on ADC value as brain MR parameters and its association with BM. DWI parameters, minimum ADC and normalized ADC ratio, for the solid BM was reported to predict the EGFR mutation status in BM from lung adenocarcinoma, and minimum ADC and ADC transition coefficient (ATC, ADC changes at the brain-metastasis interface) as predictor for OS. We found that the high prevalence of intratumoral hemorrhage or necrosis in BM is a major technical issue, and small BM was only detected on 3D T1 imaging and too small to be measured on ADC map. Therefore, we did not include ADC value as a brain MRI characteristic in the current study. There are limited data in the literature about the impact of brain MRI morphologic findings and enhancement patterns of the metastatic brain lesions on outcome. The real-world treatment experiences of EGFR-TKIs on brain metastatic NSCLC with common EGFR mutation have been reported, but few focusing on the neuroradiological appearance of BM and treatment efficacy. Brain tumors intersecting major white matter tracts such as the cortico-spinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and anterior thalamic radiations are associated with decreased OS and PFS because of direct infiltration routes to the brain stem and other structures for vital physiological function. The prior studies showed that tumor location associated with different BBB permeability, which could result in various treatment outcome.[17,18] The neuroradiologic appearance of tumor necrosis and rim enhancement is suggestive of neovascularization and rapid tumor growth, followed by lack of blood supply into the tumor and tissue hypoxia, resulting in reduced radiosensitivity and compromised penetration of therapeutic agents.[19–22]
Literature review of first and second generations EGFR-TKIs treatment in EGFR-mutated NSCLC with BM was summarized in Table 4. Recently, studies have revealed comparable OS and PFS among different EGFR-TKIs, gefitinib, erlotinib, and afatinib, but direct comparison between afatinib, gefitinib, and erlotinib as first-line therapies for advanced NSCLC with de novo BM is still lacking. It is believed that intracranial metastasis consists of brain parenchymal and leptomeningeal metastasis. Certain studies demonstrated that erlotinib showed better outcome than gefitinib in patients with BM patients with EGFR-sensitizing mutations.[24,25] Preclinical and retrospective data showed that erlotinib provides better penetration rate in the central nervous system and objective responses in patients with BM from EGFR-mutated NSCLC than gefitinib or afatinib.[4,26–32] Afatinib has also been documented to have substantial cerebrospinal fluid concentration because of its high affinity and irreversible binding as a second generation tyrosine-kinase inhibitor (TKI), and effective in patients with EGFR-mutated NSCLC with BM. The regression of CNS metastases observed during afatinib treatment has provided evidence that afatinib concentration in the CSF is sufficient to inhibit tumor growth due to its potency at relatively low concentrations. Notably, few of these studies investigated the efficacy of tyrosine-kinase inhibitor on patients with high-risk BM of EGFR-mutant advanced NSCLC. Small brain parenchymal metastasis might remain asymptomatic; leptomeningeal metastasis, the spread of malignant cells to the subarachnoid space within the compartment of the cerebrospinal fluid, often results in rapid deterioration of consciousness and performance status, and grave prognosis.[35–37] Five people diagnosed with leptomeningeal metastasis were treated with erlotinib, and the proportion of patients undergoing radiotherapy for BM was marginally higher in the afatinib group. The presence of leptomeningeal metastasis in brain MRI imaging did not contribute negatively to the survival in the erlotinib group and radiotherapy did not contribute positively in the afatinib group. Our study demonstrated that in patients with high-risk metastatic brain lesions, erlotinib provided better progression-free survival but not OS than afatinib or gefitinib.
Our study had limitations. First, it was a single center retrospective study with relatively small sample size and statistical power was therefore limited. Second, the choice among different EGFR-TKIs was based on the discretion of the healthcare providers, which could lead to selection bias. The site of progression, e.g. brain or other extracranial site, was not explicitly accounted for in our statistical analysis. In addition, after initial EGFR-TKIs treatment failure, rebiopsy to confirm the presence of the T790 M mutation is not routinely performed, thus not all patients took osimertinib (AZD9291) as second line therapy, which may potentially confound the results. Finally, the time of WBRT could influence the CNS EGFR-TKI concentration and has impact on PFS, however, there was only limited patients receiving WBRT, thus we did not further divide the patients into concurrent WBRT with EGFR-TKIs group and adjuvant WBRT after first line EGFR-TKIs failure. Future larger prospective studies are warranted to validate our study findings.
In selected patients with poor prognostic MR characteristics of BM, including tumor necrosis, rim enhancement and specific tumor locations (frontal lobe, putamen and cerebellum), erlotinib provided better PFS than afatinib or gefitinib.
Conceptualization: Chia-Ying Lin, Chao-Chun Chang, Yau-Lin Tseng, Yi-Ting Yen.
Data curation: Chia-Ying Lin, Chao-Chun Chang, Po-Lan Su, Chien-Chung Lin, Wu-Chou Su, Yi-Ting Yen.
Formal analysis: Chia-Ying Lin, Chao-Chun Chang.
Investigation: Chia-Ying Lin, Chao-Chun Chang.
Methodology: Chia-Ying Lin, Chao-Chun Chang, Po-Lan Su, Chien-Chung Lin, Yi-Ting Yen.
Resources: Po-Lan Su.
Supervision: Chien-Chung Lin, Yau-Lin Tseng, Wu-Chou Su, Yi-Ting Yen.
Writing – original draft: Chia-Ying Lin, Chao-Chun Chang.
Writing – review & editing: Yi-Ting Yen.
Chia-Ying Lin orcid: 0000-0003-3248-2369.
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brain metastasis; EGFR-tyrosine kinase inhibitors (TKIs); non-small-cell lung cancer
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